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Biomedical subjects

P Fischer

Publications and source records attributed to P Fischer.

At least 127 records · Page 7Linked to original sources
PubMed1997

Congenital myasthenic syndromes: clinical and genetic analysis of 18 patients.

Congenital myasthenic syndromes (CMS) are a group of rare gentic disorders in which neuromuscular transmission is compromised by a variety of mechanisms, other than autoimmunity. Recently, substantial progress has been made by the identification of mutations in acetylcholine receptor (AChR) genes which cause CMS. We report on the clinical and genetic analysis of 18 independent CMS patients. All patients were clinically classified as sporadic cases of CMS (group III according to ENMC consensus). In order to investigate the prevalence of AChR mutations in this group we analyzed structural domains of the AChR genes at strategically important sites - the channel pore-lining regions (M2 domains) of the alpha, beta and epsilon subunits, and the extracellular domain close the acetylcholine (ACh) binding site. All patients showed wild-type sequence in these regions, mutations were not detected. Therefore, we conclude, that point mutations in domains which are known to cause slow channel congenital myasthenic syndromes (SCCMS) are rare in group III-patients in Germany. Determining the genetic defects causing CMS may have implications for diagnosis and genetic counseling of CMS patients. Moreover, this may be important for the therapeutic management of CMS as some patients may profit form quinidine sulfate. Therefore, further efforts will be undertaken to elucidate the underlying defects of CMS.

Adolescent↗
PubMed1997

Birth weight and cognitive function in young adult life: historical cohort study.

OBJECTIVE: To examine the relation between birth weight and cognitive function in young adult life. DESIGN: Retrospective cohort study based on birth registry data and cognitive function measured during evaluation for military service. SUBJECTS: 4300 Danish conscripts born between 1973 and 1975. MAIN OUTCOME MEASURES: Mean score in the Boerge Prien test of cognitive function; score is the number of correct answers to 78 questions and correlates with full scale intelligence quotient (IQ). RESULTS: Mean score in the Boerge Prien test increased from 39.9 at a birth weight of < or = 2500 g to 44.6 at a birth weight of 4200 g even after adjustment for gestational age and length at birth, maternal age and parity, and other variables. Above a birth weight of 4200 g the test score decreased slightly. CONCLUSION: Birth weight is associated with cognitive performance in young adult life. Interference with fetal growth may influence adult cognitive performance.

Adolescent↗
PubMed1997

The yeast mic2 mutant is defective in the formation of mannosyl-diinositolphosphorylceramide.

The mic2 mutation dominantly blocks formation of mannosyl-diinositolphosphorylceramide, the most abundant sphingolipid of the yeast, Saccharomyces cerevisiae. Interestingly, lack of mannosyl-diinositolphosphorylceramide is not lethal but is compensated for by increased amounts of inositolphosphorylceramide and mannosyl-inositolphosphorylceramide in the plasma membrane and Golgi of the mutant. The level of negatively charged phospholipids in the plasma membrane of the mic2 strain is markedly reduced; the sterol composition is not altered. In spite of dramatic changes of its lipid composition the mutant grows like wild type on complex and minimal media, under osmotic stress conditions, at low pH, and in the presence of high ionic strength. While sensitivity to several drugs is not altered, the mic2 mutant strain becomes resistant to the polyene antibiotic nystatin.

Cell Membrane↗
PubMed1997

[Electroconvulsive therapy in clinical practice].

Between September 1st, 1994, and the end of August, 1995, 3% of all inpatients (21 of 731) were treated with electroconvulsive therapy (ECT) at the Department of General Psychiatry at the University Hospital for Psychiatry in Vienna. These patients suffered from psychotic and/or therapy-resistant depression (n = 15), therapy-resistant schizoaffective psychosis (n = 3), and catatonic schizophrenia (n = 3). ECT was administered in short-time anaesthetised and muscle relaxed patients. On average, each patient was treated with ECT on 9 non-consecutive days. As a rule, electrodes were placed unilaterally over the non-dominant hemisphere at the beginning. In four cases electrodes were placed bifronto-temporally. To be considered as effective the seizure had to last for at least 25 s. In shorter seizure duration ECT was repeated up to a maximum of three times in one session. With this procedure a reduction in clinical global impressions of -3.7 points was achieved in ECT-treated patients, who had been considered to be "severely" to "most severely" ill according to CGI before starting ECT. ECT proved to be effective for treating severe depression and catatonic schizophrenia, with only minor and reversible side effects. For establishing a favorable relation between good clinical outcome and remarkable few side effects, the following factors seem to be of importance, in accordance with the literature: (1) application of biphasic short-impulse stimuli in anaesthetised and muscle relaxed patients; (2) measurement of static impedance to avoid high skin impedance and short circuits. (3) at the beginning of each ECT series unilateral electrode placement over the non-dominant hemisphere; (4) ECT three times weekly on non-consecutive days.

Adult↗
PubMed1997

IgG rheumatoid factors isolated by the surface-displaying phage library technique.

Our analysis of IgG rheumatoid factors (RFs) from three patients with rheumatoid arthritis (RA) revealed that most contained significant numbers of skewed mutations per V region, suggesting that these RFs arose from antigen-driven responses. To further study IgG RFs in RA, we used pComb3 vector to construct an IgG1,lambda combinatorial antibody library from a synovial fluid sample. After panning against human IgG, Fab fragments from 71/96 phage clones bound to Fc-coated wells. Sequence analysis of 20 randomly chosen Fc-binders showed that 17 (85%) clones had identical heavy (H) and light (L) chain V regions, represented by Humha311 and Humla211, respectively. Of the remaining three clones, two had the same Humla211 L chain, but each with a different H chain V region. All the putative germline V genes for these RFs also encode RF in RA patients. However, none of these RF V regions are similar to those of the two IgG RFs derived by the hybridoma technique from the same synovial fluid. The Humha311 H chain has two frameshifts: a one-base insertion upstream of the JH region and a four-base deletion near the end of the CH1 region, resulting in a mainly unconventional amino acid sequence in the CH1 region. In the future, it will be important to study the presence of IgG molecules with such unconventional CH1 amino acid sequences, and the effects of these amino acid sequences on the structures and immunological properties of the IgG molecules.

Amino Acid Sequence↗
PubMed1997

Distribution of mast cells and their correlation with inflammatory cells around Onchocerca gutturosa, O. tarsicola, O. ochengi, and O. flexuosa.

In recent years, bovine Onchocerca species have been used as models for human onchocerciasis in drug screens. They have been suggested for immunology studies and evaluation of vaccine candidates. Therefore, mast cells and their association with other inflammatory cells were studied in five onchocercal species of cattle and deer using immunohistology. Intact mast cells occurred in large numbers in the capsule and septae of nodules, in fibrous tissue adjacent to nonnodular worms, and perivascularly. Inactive and, more frequency, activated and degranulating mast cells were observed within infiltrates in the nodule center or around nonnodular filariae. They were not detected in direct contact with the cuticle of adult worms or of microfilariae or among the macrophages, giant cells, and neutrophils forming the innermost layer around the worms. Eosinophils, but not mast cells, were obviously associated with microfilariae-producing females. The distribution, frequency, and activity of mast cells were similar for all five species and O. volvulus.

Animals↗
PubMed1997

Occurrence and diagnosis of Mansonella streptocerca in Uganda.

During filaria surveys Mansonella streptocerca was found for the first time in Uganda, in 12 widely scattered villages in the Bundibugyo district between the Ruwenzori mountains and the Ituri forest, an area not endemic for Onchocerca volvulus. The crude prevalence in 806 examined adult persons ranged from 5 to 89% with an average of 61%. In 148 children the prevalence was 36%. The geometric mean of microfilaria (mf) densities in adult mf carriers was 1.7 mf/mg skin and the community microfilarial loads ranged from 1.0 to 13.7 mf/skin snip. In 476 persons skin snips from the shoulder contained mf in 58% and those from the buttocks in 48%. Skin snips from 68 persons digested with collagenase showed that only 30-37% of the mf emerged during 24 h incubation at 30 degrees C in isotonic salt solution. An itching acute or more often chronic papular dermatitis, predominantly on the upper parts of the body, was the typical skin lesion observed in 24% of 177 M. streptocerca mf carriers.

Adolescent↗
PubMed1997

Blood transferrin and ferritin in Alzheimer's disease.

In the present study we found a significant correlation between severity of dementia of Alzheimer's type (DAT) and both transferrin and ferritin serum levels. Levels of transferrin in serum of 41 DAT patients tended to be lower than those of 19 age-matched controls, while levels of ferritin were not significantly different in DAT patients compared to controls. These results are interpreted in line with previous findings of higher brain ferritin and lower brain transferrin levels in DAT and are a circumstantial support for the oxygen radical hypothesis of degenerative brain disease.

Aged↗
PubMed1997

The effect of intestinal bacteria adherence on drug diffusion through solid films under stationary conditions.

PURPOSE: To study the in vitro and in vivo the role of surface bacterial adhesion on the diffusion of model drugs at stationary conditions. METHODS: Salicylic acid (SA) diffusion through ethyl cellulose (EC) films was measured in vitro in side-by-side diffusion cells with and without E. coli of intestinal origin. Insulin (I) release from paper strips coated or uncoated with pectin films, with or without antibiotic treatment, was measured in vivo in conscious rats after cecal implantation by comparing blood glucose levels at Tmax of the pharmacodynamic effect. RESULTS: During five hours of diffusion studies which were performed immediately following incubation of EC films with bacteria, the diffusion rate of SA throughout the films was 2.72-fold lower in the presence of bacteria compared with the diffusion rate in the control studies conducted without bacteria. The mean blood glucose levels dropped in the rat to 40.6 +/- 21.6% of glucose basal levels within 2.4 +/- 1.4 h when uncoated I solid carriers were used. Glucose levels did not change for pectin-coated dosage forms. After antibiotic treatment which prevented the formation of bacterial biofilm on the surface of the I solid dosage forms, blood glucose levels dropped to 22.0 +/- 4.7% and 50.9 +/- 20.5% of glucose basal levels within 7.4 +/- 2.6 h and 1.8 +/- 0.9 h for pectin uncoated or coated dosage forms, respectively. Maximum bacterial adherence occurred at stationary conditions (RPM = 0), while at maximum agitation (200 RPM), almost no adherence occurred. CONCLUSIONS: (a) Bacterial adherence shows down the diffusion rate of SA through EC films; (b) Under stationary conditions bacterial adherence may also interfere with drug release from biodegradable (pectin) films; (c) Successful functioning of biodegradable colon-specific delivery systems depends on agitation and surface friction in the lumen of the colon.

Animals↗
PubMed1997

Continued increase in prevalence of obesity in Danish young men.

BACKGROUND: Previous studies of Danish young men showed a steep increase of obesity since the birth years of the early 1940s with a levelling off in the 1950s. OBJECTIVE: To study the current prevalence of obesity and its recent changes in Danish young men. DESIGN: Cross-sectional study based on weight and height measured at the military board for the birth cohorts 1955, 1965 and 1973-75. SUBJECTS: We obtained information from the old paper files comprising the two cohorts of men born in 1955 (6549 adults) and 1965 (6404 adults) and prospectively examined 4300 from the birth cohorts 1973-75 in a conscription district in Denmark during the period 1 August 1993 to 31 July 1994. RESULTS: The prevalence of obesity (defined as body mass index (BMI) > or = 30 kg/m2) was 1.5% in 1955, 2.1% in 1965 and 4.6% in 1973-75 birth cohorts. The median BMI has increased during the period from 21.7-22.8 kg/m2. CONCLUSION: Obesity is relatively common and has increased among Danish young men.

Adult↗
PubMed1997

Immunohistochemical differentiation of metastases of renal carcinomas versus other carcinomas with anti-gamma GT monoclonal antibody 138H11.

AIMS: Adenocarcinomas account for about 60% of metastatic cancers of unknown primary (CUP) site. In such a clinical CUP situation, histopathologists are challenged to differentiate renal cell carcinomas (RCC) from other adenocarcinomas with similar immunophenotypes, especially chemotherapeutically treatable mammary and ovarian carcinomas. METHODS AND RESULTS: Recently, we produced a monoclonal antibody (mAb), designated 138H11, against human gamma-glutamyl-transferase (gamma GT), which stained over 98% primary clear cell and chromophilic RCC on frozen sections. The 138H11 epitope could not be stained using conventional techniques in most paraffin-embedded sections of the same origin, due to destruction by formalin fixation below the detection level. Here, we demonstrate that mAb 138H11 can specifically stain gamma GT in paraffin-embedded primary and metastatic RCC after enhancement with an ultrasensitive immunohistochemical method. We analysed a selected subgroup of adenocarcinomas with immunophenotypes which would not allow a differentiation from RCC in a CUP situation. We found a predominantly membranous expression of the 138H11 target antigen in 26/51 primary RCC and 15/ 34 metastatic RCC. In contrast, all 43/43 primary ovarian and bronchial carcinomas as well as 54/54 metastases of ovarian, mammary, bronchial and gastric carcinomas were negative for mAb 138H11. CONCLUSIONS: The data suggest that mAb 138H11 is useful for the immunohistochemical differentiation of RCC from other metastatic adenocarcinomas if the primary site of the tumour is not known.

Antibodies, Monoclonal↗
PubMed1997

Treatment of human Mansonella streptocerca infection with ivermectin.

We studied the short-term effects of a single dose of 150 micrograms/kg body weight ivermectin on Mansonella streptocerca in an area endemic for streptocerciasis, but not for onchocerciasis, in western Uganda. Six and 12 days after treatment no microfilaria (mf) were found in the skin of 53 out of 96 mf carriers living in 3 villages, and the geometric means of the mf densities of remaining mf carriers were only 33-40% of pretreatment levels. This reduction of mf density was highly significant (P < 0.0001). Immunohistological examination of skin biopsies showed degenerated and disintegrating mf surrounded by activated eosinophils (positive for activated cationic protein), macrophages, and neutrophils (positive for myeloperoxidase and defensin) on day 6 after treatment. Remarkable was the invasion of young, L1 protein-positive macrophages and the release of neutrophil defensin as signs of acute inflammation. We conclude that ivermectin has a strong microfilaricidal activity against M. streptocerca. Common adverse effects were increased pruritus and acute papular dermatitis in 45% of 86 mf carriers on day 6 after treatment. No serious adverse side-effects were noticed in about 700 treated persons.

Adult↗
PubMed1997

Catabolism of 3-Nitrophenol by Ralstonia eutropha JMP 134.

Ralstonia eutropha JMP 134 utilizes 3-nitrophenol as the sole source of nitrogen, carbon, and energy. The entire catabolic pathway of 3-nitrophenol is chromosomally encoded. An initial NADPH-dependent reduction of 3-nitrophenol was found in cell extracts of strain JMP 134. By use of a partially purified 3-nitrophenol nitroreductase from 3-nitrophenol-grown cells, 3-hydroxylaminophenol was identified as the initial reduction product. Resting cells of R. eutropha JMP 134 metabolized 3-nitrophenol to N-acetylaminohydroquinone under anaerobic conditions. With cell extracts, 3-hydroxylaminophenol was converted into aminohydroquinone. This enzyme-mediated transformation corresponds to the acid-catalyzed Bamberger rearrangement. Enzymatic conversion of the analogous hydroxylaminobenzene yields a mixture of 2- and 4-aminophenol.

Journal Article↗
PubMed1997

Dose escalation of cyclophosphamide in patients with breast cancer: consequences for pharmacokinetics and metabolism.

PURPOSE: The alkylating anticancer agent cyclophosphamide (CP) is a prodrug that undergoes a complex metabolism in humans producing both active and inactive metabolites. In parallel, unchanged CP is excreted via the kidneys. The aim of this study was to investigate the influence of dose escalation on CP pharmacokinetics and relative contribution of activating and inactivating elimination pathways. PATIENTS AND METHODS: Pharmacokinetics of CP were assessed in 12 patients with high-risk primary breast cancer who received an adjuvant chemotherapy regimen that included four courses of conventional-dose CP (500 mg/m2 over 1 hour every 3 weeks) followed by one final course of high-dose CP (100 mg/kg over 1 hour). Plasma concentrations of CP were analyzed by high-performance liquid chromatography (HPLC), 24-hour urinary concentrations of CP, and its inactive metabolites (carboxyphosphamide, dechloroethylcyclophosphamide [dechlorethylCP], ketocyclophosphamide [ketoCP]) were determined by 31-phosphorus-nuclear magnetic resonance (31P-NMR)-spectroscopy. RESULTS: There was no difference in dose-corrected area under the concentration-time curve (AUC) (216 v 223 [mumol.h/[mL.g]), elimination half-life (4.8 v 4.8 hours), systemic clearance (79 v 77 mL/min) and volume of distribution (0.49 v 0.45 L/kg) of CP between conventional- and high-dose therapy, respectively. However, during high-dose chemotherapy, we observed a significant increase in the renal clearance of CP (15 v 23 mL/min; P < .01) and in the formation clearance of carboxyphosphamide (7 v 12 mL/min; P < .05) and dechloroethylCP (3.2 v 4.2 mL/min; P < .05), whereas metabolic clearance to ketoCP remained unchanged (1.3 v 1.2 mL/min). Consequently, metabolic clearance to the remaining (reactive) metabolites decreased from 52 to 38 mL/min (P < .001). The relative contribution of the different elimination pathways to overall clearance of CP demonstrated wide interindividual variability. CONCLUSION: Overall pharmacokinetics of CP are apparently not affected during eightfold dose escalation. However, there is a shift in the relative contribution of different clearances to systemic CP clearance in favor of inactivating elimination pathways, thereby indicating saturation of bioactivating enzymes during dose escalation. Besides individual enzyme capacity, hydration and concomitant medication with dexamethasone modulated CP disposition.

Adult↗
PubMed1997

Meta-analysis of the Hachinski Ischemic Score in pathologically verified dementias.

Our objectives were to investigate the utility of the Hachinski Ischemic Score (HIS) in differentiating patients with pathologically verified Alzheimer's disease (AD), multi-infarct dementia (MID), and "mixed" (AD plus cerebrovascular disease) dementia, and to identify the specific items of the HIS that best discriminate those dementia subtypes. Investigators from six sites participated in a meta-analysis by contributing original clinical data, HIS, and pathologic diagnoses on 312 patients with dementia (AD, 191; MID, 80; and mixed, 41). Sensitivity and specificity of the HIS were calculated based on varied cutoffs using receiver-operator characteristic curves. Logistic regression analyses were performed to compare each pair of diagnostic groups to obtain the odds ratio (OR) for each HIS item. The mean HIS (+/- SD) was 5.4 +/- 4.5 and differed significantly among the groups (AD, 3.1 +/- 2.5; MID, 10.5 +/- 4.1; mixed, 7.7 +/- 4.3). Receiver-operator characteristic curves showed that the best cutoff was < or = 4 for AD and > or = 7 for MID, as originally proposed, with a sensitivity of 89.0% and a specificity of 89.3%. For the comparison of MID versus mixed the sensitivity was 93.1% and the specificity was 17.2%, whereas for AD versus mixed the sensitivity was 83.8% and the specificity was 29.4%. HIS items distinguishing MID from AD were stepwise deterioration (OR, 6.06), fluctuating course (OR, 7.60), hypertension (OR, 4.30), history of stroke (OR, 4.30), and focal neurologic symptoms (OR, 4.40). Only stepwise deterioration (OR, 3.97) and emotional incontinence (OR, 3.39) distinguished MID from mixed, and only fluctuating course (OR, 0.20) and history of stroke (OR, 0.08) distinguished AD from mixed. Our findings suggest that the HIS performed well in the differentiation between AD and MID, the purpose for which it was originally designed, but that the clinical diagnosis of mixed dementia remains difficult. Further prospective studies of the HIS should include additional clinical and neuroimaging variables to permit objective refinement of the scale and improve its ability to identify patients with mixed dementia.

Brain Ischemia↗